Spirocyclic nucleoside analogues for the treatment of hepatitis e

Abstract

The present disclosure is directed toward spirocyclic nucleoside analogs, compositions comprising these compounds, and their use for treating hepatitis E infections.

1 . A method of treating a hepatitis E virus (HEV) infection in a subject in need thereof, comprising administering a compound of formula (I) to the subject: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
       
       wherein:
 Base is (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), or(b-8): 
 
       
         
           
           
               
               
           
         
         X is O or S; 
         R 1  is H, F, or N 3 ; and 
         R 2  is (f-1) or (f-2): 
       
       
         
           
           
               
               
           
         
       
       and
 R 3  is C 1-4 alkyl. 
 
     
     
         2 . The method of  claim 1 , wherein Base is (b-1). 
     
     
         3 . The method of  claim 1 , wherein R 2  is (f-1). 
     
     
         4 . The method of  claim 1 , wherein Base is (b-1), X is S, R 2  is (f-1) and R 3  is isopropyl. 
     
     
         5 . The method of  claim 1 , wherein Base is (b-1), X is O, R 2  is (f-1) and R 3  is butyl. 
     
     
         6 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . A pharmaceutical composition for treating a hepatitis E virus infection in a subject in need thereof, comprising administering a compound of formula (I) to the subject: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof: 
       
       wherein:
 Base is (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), or (b-8): 
 
       
         
           
           
               
               
           
         
         X is O or S; 
         R 1  is H, F, or N 3 ; and 
         R 2  is (f-1) or (f-2): 
       
       
         
           
           
               
               
           
         
         R 3  is C 1 -4alkyl; 
         and a pharmaceutically acceptable vehicle. 
       
     
     
         8 . The method of  claim 1 , wherein the hepatitis E virus infection is a chronic HEV infection. 
     
     
         9 . The method of  claim 1 , wherein the HEV virus infection is of genotype 1, genotype 2 or genotype 3. 
     
     
         10 . The method of  claim 1 , wherein the subject is a pregnant woman, an immune-compromised subject or immune-deficient subject. 
     
     
         11 . The pharmaceutical composition  claim 7 , wherein the hepatitis E virus infection is a chronic HEV infection. 
     
     
         12 . The pharmaceutical composition of  claim 7 , wherein the HEV virus infection is of genotype 1, genotype 2 or genotype 3. 
     
     
         13 . The pharmaceutical composition of  claim 7 , wherein the subject is a pregnant woman, an immune-compromised subject or immune-deficient subject.